We sought to identify risk factors and neonatal outcomes associated with the failure of the INSURE method ( INtubation- SURfactant- Extubation) during nasal continuous positive airway pressure for preterm infants with respiratory distress syndrome. We used a retrospective analysis of the prenatal histories, clinical courses, and laboratory data of all inborn infants with gestational age 27 to 34 weeks and respiratory distress syndrome treated with INSURE method. Infants were categorized into two groups: INSURE failure group and INSURE success group. One hundred nine infants were eligible to the study. INSURE failure was registered in 35 infants (32.1%). After control for confounding variables, INSURE failure was significantly associated with arterial partial pressure of carbon dioxide (adjusted odds ratio [OR] = 1.82; 95% confidence interval [CI] = 1.76 to 90.56), mean arterial-to-alveolar oxygen tension ratio (adjusted OR = 1.13; 95% CI = 1.06 to 85.34) and severe radiological grade (adjusted OR = 1.31; 95% CI = 1.15 to 70.16). Positive predictive values of these variables were 70, 75, and 55%, respectively. Patent ductus arteriosus and mortality rates were significantly higher in INSURE failure group. Arterial partial pressure of carbon dioxide, arterial-to-alveolar oxygen tension ratio, and severe radiological grade are predictors of the failure of INSURE method in preterm infants with respiratory distress syndrome. However, a prospective randomized controlled trial is needed to determine whether or not infants at risk for INSURE failure are better off being treated with mechanical ventilation.